Synthesis of 2, 6-dicarbonylpyridines

ABSTRACT

Synthesis of 2,6-dicarbonylpyridines in solution in a hydrocarbon medium is described. The hydrocarbon medium solutions of 2,6-dicarbonylpyridines may be used directly in further syntheses.

FIELD OF THE INVENTION

[0001] This invention relates to the synthesis of 2,6-dicarbonylpyridinedihalides and to conversion of such dihalides to2,6-dicarbonylpyridines. More specifically, this invention relates tothe synthesis of 2,6-diacetylpyridine.

BACKGROUND OF THE INVENTION

[0002] 2,6-diacetylpyridine has been prepared from reaction of pyridine2,6-dicarboxylic acid diethyl ester and ethyl acetate in the presence ofsodium ethoxide, ethanol and xylene. See Lukes, et al., Collect. CzechChem. Commun. 24:36 (1959). A 55% to 57% yield for this reaction isreported by Terentew, et al., Zh.Vses.Khim.O'va im.D. I.Mendeleeva 6:116(1961) (Abstract), CAOLD Abstract CA 55:144501. An analogous, presentlycommercial, multi-step synthesis is generally illustrated by Equation 1:

[0003] 2,6-diacetylpyridine in about 50% yield may be extracted bysolvent exchange from the reaction mixture.

[0004] Yamamoto, Chem.Pharm.Bull. 43:1028-1030 (1995) reports a 59%yield of 2,6-diacetylpyridine by reaction of 2,6-bis(trimethyl stannyl)pyridine with 2-oxo-propenyl chloride. Reaction of 2,6-pyridine carbonylchloride with methyl lithium in the presence of CuI at −78° C. in THF issaid to provide a 93% yield of 2,6-diacetylpyridine. Jiang, et al.,Tetrahedron Lett. 37(6):797-800 (1996). Organocupritic intermediatesdecompose rapidly if a uniform low temperature, impractical in a largereactor, is not maintained.

[0005] There is a need for a cost effective synthesis free of lowtemperature parameters that provides a high yield of2,6-diacetylpyridine in a reaction mixture which may but need not beused directly in further syntheses.

SUMMARY OF THE INVENTION

[0006] Pursuant to one specific aspect of the invention, a 2,6-pyridinedicarboxylic acid is converted to a corresponding 2,6-dicarbonyldichloride in hydrocarbon solution. The dichloride is converted in situto a 2,6-pyridine-bis(2-alkoxyalkyl) carboxamide. The carboxamide may betreated sequentially first with a hydrocarbyl alkali metal salt, andthereafter with a trialkyl silicon halide. Treatment of the consequentreaction mixture with water yields a biphasic solution comprising anaqueous bottom layer and an organic top layer containing the desired2,6-dicarbonylpyridine. An additional quantity of 2,6-dicarbonylpyridinemay be recovered from the aqueous layer by extraction with toluene.

GENERAL DESCRIPTION OF THE INVENTION

[0007] Pursuant to a typical first step of the invention, a 2,6-pyridinedicarboxylic acid is converted in known manner to any corresponding2,6-pyridine dicarboxylic dihalide, preferably the dichloride. Forexample, the 2,6-pyridine dicarboxylic acid may be treated with asulfonyl halide, such as sulfonyl chloride, in a hydrocarbon medium,preferably toluene, for a time and under conditions effective to yield asolution of the corresponding 2,6-pyridine dicarboxylic acid dihalide inthe hydrocarbon medium.

[0008] The hydrocarbon medium solution of 2,6-pyridine dicarboxylic aciddihalide may be taken up in a C₁ to C₅ alkyl halide, preferablymethylene chloride, medium and treated with a bis(2-alkoxyalkyl) amine,preferably bis(2-methoxyethyl) amine, and a C₁ to C₅ trialkyl amine toproduce a reaction mixture comprising 2,6-pyridine dicarboxamide in amixed hydrocarbon and alkyl halide medium. The bis(2-alkoxyalkyl) amineand the trialkyl amine are preferably premixed but may be addedseparately in any desired sequence. The alkyl halide component of thismixed medium may be stripped from the reaction mixture to provide asolution of the 2,6-pyridine dicarboxamide in the residual hydrocarbon.

[0009] A second step of the invention may comprise treatment of thehydrocarbon solution of 2,6-pyridine dicarboxamide from the first stepwith an alkyl or aryl alkali metal salt having the formula MZ, in whichM is any alkali metal, and Z is any alkyl or aryl group. Preferably, Zis a C₁ to C₆ alkyl group or a C₆ to C₁₀ substituted or unsubstitutedaryl group. Methyllithium is preferred. A typical second step reactionis illustrated by Equation 2:

[0010] The reaction of the carboxamide with the alkali metal saltproceeds in two stages.

[0011] In a first stage, the exotherm may be controlled to provide a pottemperature range of −25° C. to −15° C. The pot temperature of the firststage reaction mixture is preferably adjusted to and maintained at atemperature of −10° C. to −30° C. for a short time, for example, for 15to 45 minutes, and thereafter cooled to a pot temperature in the rangeof −10° C. to −20° C. The cooled first stage reaction mixture may betreated with any desired trialkylsilyl halide, typically trimethylsilylchloride (TMSCl), in a hydrocarbon medium as the consequent exotherm iscontrolled to provide and maintain a pot temperature in the range of−10° C. to 10° C.

[0012] The second stage reaction is generally illustrated by Equation 3:

[0013] The second stage reaction mixture is a slurry in the first stagehydrocarbon medium. It may be transferred to a separate vesselcontaining iced water as the exotherm is controlled to provide andmaintain a pot temperature of 0° C. to 15° C. The reaction isillustrated by Equation 4:

[0014] The pot temperature of the consequent biphasic solutioncomprising an aqueous bottom layer and an organic top layer may beadjusted to room temperature. The organic top layer comprises ahydrocarbon solution of the desired 2,6-dicarbonylpyridine. The aqueousbottom layer may be separated and washed with toluene to provide anextract containing an additional quantity of 2,6-dicarbonylpyridinewhich may be added to the separated organic top layer. Yields range from85% to 90% by weight based on the 2,6-dicarboxylic acid startingmaterial. Overall yields of 2,6-dicarbonylpyridine typically are 80-83%by weight.

[0015] The hydrocarbon solution of 2,6-dicarbonylpyridine may be useddirectly in other syntheses. Pursuant to a typical such synthesis, a 1liter flask equipped with a Dean-Stark trap was charged with2,6-diacetylpyridine produced by the method of this invention (27% by wtin toluene, 0.1 mol, 60 g), acetic acid (1 g), and2,4,6-trimethylaniline (0.4 mol, 54 g). The mixture was heated to refluxfor 12-18 hours, whereupon the theoretical amount of water was collectedin the trap. The toluene was stripped under high vacuum, and n-butanol(100 mL) was added to the remaining oil. The alcoholic yellow slurry washeated to 100° C. for 10 minutes and slowly cooled to room temperature.The yellow crystalline solids were filtered, and the solids were washedwith n-butanol and dried. Yield: 80-85%. The reaction is illustrated byEquation 5:

EXEMPLIFICATION OF THE INVENTION EXAMPLE 1

[0016] Step 1: Synthesis of 2,6-Pyridine Dicarboxamide

[0017] A 5L flask, charged with 2,6-pyridine dicarboxylic acid (167 g, 1mol), toluene (400 mL), and thionyl chloride (594 g, 5 mol), wasrefluxed. The excess thionyl chloride was atmospherically stripped sothat the pot temperature was held at 120° C. to 130° C. for 30 minutes.Toluene (1 L) was added back, and the mixture was atmosphericallystripped to remove most of the thionyl chloride. See Equation 6:

[0018] In the reaction illustrated by Equation 6, any pyridinedicarboxylic acid in which the carbonyl groups have from 1 to 10 carbonatoms may be used. The two carbonyl groups may be at any availablepyridine ring position. Ring positions not occupied by carbonyl groupsmay have any other desired substituents. C₁ to C₁₀ alkyl substituentsare preferred.

[0019] The intermediate 2,6-pyridine diacetyl chloride (in about 200-300mL of toluene) was cooled to room temperature and taken up into CH₂Cl₂(1 L). The yield of 2,6-diacetyl chloride was quantitative.

[0020] The CH₂Cl₂ solution was cooled (−20° C.), and treated with apremixed solution of bis(2-methoxyethyl) amine (270 g, 2.03 mol) andtriethylamine (253 g, 2.5 mol) as fast as the exotherm would allow (−20to +10° C.). After the addition was completed, the slurry was agitatedfor 30 minutes at room temperature. Water (1 L) was added to the slurry,the organic top layer was separated, the aqueous bottom layer was washedwith CH₂Cl₂ (3×400 mL washes), the combined extracts were dried oversodium sulfate, and filtered. The filtrate was atmospherically strippedto remove all of the CH₂Cl₂, leaving behind a toluene solution (30-40 wt%) of the 2,6-pyridine dicarboxamide. The yield of 2,6-pyridinedicarboxamide was 93-97% by weight.

[0021] Any bis(2-alkoxyalkyl) amine in which the alkoxy or alkyl groupseach separately may have from 1 to 10 carbon atoms and any trialkylaminein which the alkyl groups have from 1 to 8 carbon atoms may be used.

[0022] Step 2: Conversion of 2,6-pyridine dicarboxamide to2,6-diacetylpyridine

[0023] The step 1 reaction mixture (2,6-pyridine dicarboxamide) (372 gas a 35 wt % solution in toluene, 0.937 mol) was cooled (−25° C.) andMeLi (1.4 M, 1.97 mol, 2.1 equivalents, 1.4 L) was added as fast as theexotherm would allow (temperature range −25° C. to −15° C.). After theaddition, the solution was warmed to −10 to −5° C. for 30 minutes, thesolution was cooled (−10° C.), and treated with trimethylsilyl chloride(TMSCl) (611 g, 5.62 mol) (see Equation 3) as fast as the exotherm wouldallow (−10 to +10° C.). The resulting slurry was warmed to roomtemperature for 30 minutes and cooled (−10° C.). The slurry wastransferred to a flask containing iced water (1.5 L) as fast as theexotherm maintained at 0 to 15° C. would allow. The biphasic solutionwas warmed to room temperature, the organic top layer was separated, theaqueous bottom layer was washed (3×350 Ml) with toluene, and thecombined extracts were dried over sodium sulfate and filtered. Thefiltrate was atmospherically stripped to remove hexamethyldisiloxanewhich resulted from the reaction of trimethylsilyl chloride with water(Equation 7):

2Me₃SiCl+H₂O→Me₃SiOSiMe₃+2HCl   EQUATION 7

[0024] and polish-filtered at room temperature so that the desiredproduct remained in toluene as a solution (25 to 30 wt %) usefuldirectly in subsequent syntheses. Yields range from 85 to 90%, and theoverall yields from 2,6-pyridine dicarboxylic are 80-83%. Any alkyl oraryl alkali metal salt heretofore described may be used instead ofmethyllithium. Any desired trialkyl silicon halide may be used insteadof trimethylsilyl chloride.

I claim:
 1. A process for the synthesis of 2,6-dicarbonylpyridine whichcomprises: (i) converting 2,6-pyridine dicarboxylic acid to a solutionof 2,6-pyridine dicarboxylic acid dichloride in a hydrocarbon; (ii)treating said step (i) hydrocarbon solution of 2,6-pyridine dicarboxylicdichloride with a preformed mixture of bis(2-alkoxy alkyl) amine andtrialkyl amine, wherein a reaction mixture comprising a solution of2,6-pyridine dicarboxamide in said step (i) hydrocarbon is produced;(iii) treating said step (ii) reaction mixture solution with a compoundof formula MZ, wherein M is an alkali metal and Z is an alkyl or arylgroup, and trialkylsilyl halide, wherein a step (iii) reaction mixtureis produced; and (iv) treating said step (iii) reaction mixture withwater wherein a biphasic step (iv) reaction mixture is produced; whereinsaid step (iv) reaction mixture comprises a lower aqueous layer and anupper organic layer, and wherein said upper organic layer comprises ahydrocarbon solution of 2,6-dicarbonylpyridine.
 2. The method of claim 1further comprising a step (v) utilizing said step (iv) hydrocarbonsolution of 2,6-dicarbonylpyridine directly in a further synthesis. 3.The method of claim 1 wherein said step (i) converting is accomplishedby treating said 2,6-pyridine dicarboxylic acid with a sulfonyl halide.4. The method of claim 1 wherein said step (ii) preformed mixturecontains about 2.0 mol of bis(methoxyethyl) amine and about 2.5 mol ofethyl amine.
 5. The method of claim 1 wherein the lower aqueous layerand the upper organic layer of said step (iv) biphasic reaction mixtureare separated, and wherein the separated lower aqueous layer is washedwith toluene to extract 2,6-dicarbonylpyridine therefrom.
 6. A methodwhich comprises: (i) treating a 2,6-pyridine dicarboxylic dihalide insolution in a hydrocarbon medium with a bis(2-alkoxyalkyl) amine and atrialkyl amine, wherein a reaction mixture containing 2,6-pyridinedicarboxamide in said hydrocarbon medium is produced.
 7. A method whichcomprises: (i) treating a 2,6-pyridine dicarboxamide in solution in ahydrocarbon medium with a compound of formula MZ in which M is anyalkali metal and Z is any alkyl or aryl group, wherein a first reactionmixture is produced, (ii) treating said step (i) first reaction mixturewith a trialkylsilyl halide, wherein a second reaction mixture isproduced, and (iii) treating said step (ii) second reaction mixture withwater, wherein a biphasic solution having an organic upper layer and anaqueous lower layer is produced, and wherein said organic upper layercomprises a solution of a 2,6-dicarbonylpyridine in said step (i)hydrocarbon medium.
 8. A method which comprises: (i) providing a slurryof 2,6-pyridine dicarboxylic acid in toluene; (ii) converting said2,6-pyridine dicarboxylic acid in situ in solution in said toluene to2,6-pyridine diacetyl dichloride, wherein a solution of 2,6-pyridinediacetyl dichloride in toluene is produced; (iii) converting said step(ii) solution to a step (iii) solution of 2,6-pyridine dicarboxamide insaid toluene; and (iv) converting said step (iii) 2,6-pyridinedicarboxamide in situ in solution in said step (iii) toluene to2,6-diacetylpyridine.
 9. The method of claim 8 further comprising a step(v) treating said 2,6-diacetylpyridine in situ in said step (iv) toluenesolution with a 2,4,6-alkyl aniline.